Hepatocyte-specific knockout of HIF-2α cannot alleviate carbon tetrachloride-induced liver fibrosis in mice

Abstract

Background The effects of hypoxia inducible factor-2α (HIF-2α) deficiency on liver fibrosis have not been demonstrated in a fibrosis model induced by carbon tetrachloride (CCl4). We aimed to examine whether hepatocyte-specific HIF-2α deletion could ameliorate CCl4-induced liver fibrosis in mice. Methods Hepatocyte-specific HIF-2α knockout mice were created using an albumin promoter-driven Cre recombinase. HIF-2α knockout (KO) mice and floxed control wild-type (WT) mice were fed a normal diet (ND) and received either twice weekly intraperitoneal injections of CCl4 solution (CCl4 dissolved in olive oil) or the corresponding amount of olive oil for 8 weeks. The indicators of liver function, glucose and lipid metabolism, and liver histology were compared among the different groups. Results Hepatocyte-specific HIF-2α knockout had no effect on the growth, liver function, glucose or lipid metabolism in mice. CCl4-treated KO and WT mice had a similar pattern of injury and inflammatory cell infiltration in the liver. Quantification of Masson staining, α-smooth muscle actin (α-SMA) immunohistochemistry, and the hydroxyproline (HYP) content revealed similar liver fibrosis levels between KO and WT mice injected intraperitoneally with CCl4. Immunohistochemistry analysis suggested that HIF-2α was mainly expressed in the portal area and hepatic sinusoids but not in hepatocytes. Bioinformatics analyses further indicated that HIF-2α expression was neither liver specific nor hepatocyte specific, and the effect of HIF-2α in hepatocytes on liver fibrosis may not be as important as that in liver sinuses. Conclusions Hepatocyte HIF-2α expression may not be a key factor in the initiation of liver fibrogenesis, and hepatocyte-specific deletion of HIF-2α may not be the ideal therapeutic strategy for liver fibrosis.

Non-alcoholic fatty liver disease combined with rheumatoid arthritis exacerbates liver fibrosis by stimulating co-localization of PTRF and TLR4 in rats

“…Hyp is an amino acid unique to collagen, and many diseases can be accompanied by changes in collagen metabolism, causing altered blood, urine, and tissue Hyp levels. Hyp levels in the liver are an important index reflecting the degree of liver fibrosis, and increased Hyp levels in the liver imply increased liver fibrosis ( Bedair et al, 2023 ; Ye et al, 2023 ). Here, we determined Hyp levels in the liver tissue of the rats and found that the Hyp level was the highest in the NAFLD + CIA group, followed by NAFLD group.…”